Apolipoprotein M promoter polymorphisms alter promoter activity and confer the susceptibility to the development of type 1 diabetes
ABSTRACT Apolipoprotein M plays an important role in the formation of prebeta-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes.
The study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay.
SNP T-778C was strongly associated with T1D in both Han Chinese (p=0.002, OR=2.188, CI 95%=1.338-3.581) and Swedish (p=0.021, OR=2.865, CI 95%=1.128-7.278) populations. The luciferase activity of -778C promoter was 1.41 times as high as that of -778T promoter (9.90+/-1.92 vs. 7.04+/-0.76, p=0.001).
Allele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.
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ABSTRACT: Aims/IntroductionSphingosine-1-phosphate (S1P), a multifunctional bioactive lipid mediator, is involved in various diseases. Apolipoprotein M (ApoM) carries S1P on high-density lipoprotein and modulates S1P metabolism to increase the total S1P mass in the body. Both S1P and ApoM are involved in diabetes.Materials and Methods The present study examined the modulation of S1P and ApoM levels in the plasma, liver and kidneys in streptozotocin-induced diabetes (STZ) mice, and the effects of insulin on the S1P and ApoM levels in the plasma and liver in STZ mice and normal mice. We also examined the effects of insulin and glucose on the ApoM levels in HepG2 cells.ResultsIn STZ mice, both the plasma S1P and ApoM levels were higher than those in control mice. The hepatic S1P and ApoM contents were also elevated. The hepatic S1P and ApoM contents were reduced by insulin treatment, whereas high-dose insulin decreased the plasma S1P and ApoM levels. In mice without streptozotocin treatment, the administration of insulin decreased the plasma S1P and ApoM levels, and the hepatic content of ApoM, whereas the hepatic level of S1P was not altered. Treatment with insulin and incubation under a low glucose level decreased the ApoM levels in HepG2 cells. Regarding the kidney, the renal levels of S1P and ApoM were increased in STZ mice, and insulin treatment partially restored this increment.Conclusions In STZ mice, the levels of S1P and ApoM in the plasma, liver, and kidneys were increased. Insulin treatment somehow reversed this modulation in STZ mice.04/2014; 5(6). DOI:10.1111/jdi.12232
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ABSTRACT: Background and Aims: Risk of type 2 diabetes mellitus (T2DM) differs according to ethnicity. Levels of apolipoprotein M (ApoM) have been shown to be decreased in T2DM. However, its role in different ethnicities is not known. We examined the differences in plasma ApoM levels in Swedish residents born in Iraq (Iraqis) and Sweden (Swedes) in relation to T2DM and insulin resistance (IR). Methods and Results: Iraqis and Swedes, aged 45 to 65 years residing in Rosengård area of Malmö were randomly selected from census records and underwent an oral glucose tolerance test. Plasma levels of ApoM were quantified in 162 participants (Iraqis, n=91; Swedes, n=71) by a sandwich ELISA method. Age-, sex-, and body mass index (BMI) adjusted plasma ApoM levels differed by country of birth, with Swedes having 18% higher levels compared to Iraqis (p=0.001). ApoM levels (mean±SD) were significantly decreased in Swedes with T2DM (0.73±0.18) compared to those with normal glucose tolerance (NGT) (0.89±0.24; p=0.03). By contrast, no significant difference in ApoM levels was found between Iraqis with T2DM (0.70±0.17) and those with NGT (0.73±0.13; p=0.41). In multivariate linear regression analysis with an interaction term between IR and country of birth, low ApoM levels remained significantly associated with IR in Swedes (p=0.008), independently of age, sex, BMI, family history of diabetes, HDL, LDL, and triglycerides, but not in Iraqis (p=0.35). Conclusion: Our results show that ApoM levels differ according to country of birth and are associated with IR and T2DM only in Swedes.Nutrition, metabolism, and cardiovascular diseases: NMCD 07/2014; In press. DOI:10.1016/j.numecd.2014.05.007 · 3.88 Impact Factor
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ABSTRACT: High-density lipoprotein (HDL) has been proposed to enhance β-cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P. We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion. ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions.Biochimica et Biophysica Acta 05/2014; DOI:10.1016/j.bbalip.2014.05.002 · 4.66 Impact Factor